It is an object of the invention to provide the novel 20,21-dinor-eburnamenines of formula I and their non-toxic, pharmaceutically acceptable salts and a novel process and novel intermediates for their preparation.
It is another object of the invention to provide novel pharmaceutical compositions and methods.
These and other objects and advantages of the invention will become obvious from the following detailed description.
The novel compounds of the invention are a compound selected from the group consistiny of all possible isomers or racemates of a compound of the formula 
wherein X1, X2 and X3 are individually selected from the group consisting of hydrogen, halogen, unsubstituted or substituted alkyl of 1 to 18 carbon atoms, unsubstituted or substituted alkenyl and alkynyl of 2 to 18 carton atoms, unsubstituted or substituted alkoxy of 1 to 7 carbon atoms, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94NH2, mono and dialkylamino of 1 to 5 alkyl carbon atoms and unsubstituted or substituted phenyl, 
R is selected from the group consisting of unsubstituted or substituted alkyl of 1 to 7 carbon atoms, unsubstituted or substituted alkenyl and alkynyl of 2 to 7 carbon atoms, unsubstituted or substituted phenyl and carboxy optionally salified or esterified, R1 is 
one of R8 and R9 is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl of 1 to 6 carbon atoms, unsubstituted or substituted alkenyl and alkynyl of 2 to 6 carbon atoms, unsubstituted or substituted phenyl, esterified carboxy, xe2x80x94CN, and acyl of 2 to 6 carbon atoms and the other and R10 are selected from the group consisting of hydrogen, unsubstituted or substituted alkyl of 1 to 6 carbon atoms, unsubstituted or substituted alkenyl and alkynyl of 2 to 6 carbon atoms and unsubstituted or substituted phenyl and its non-toxic, pharmaceutically acceptable salts with acids or bases.
In the compounds of formula I, the 3-hydrogen and the 16-hydrogen can each leave the alpha or beta configuration which determines if the compounds will be the cis or trans diastereoisomeric form.
In the compounds of formula I, halogen may be bromine or iodine but is preferably chlorine or fluorine. Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.-butyl and n-penityl and examples of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy, tert.-butoxy. Examples of monoalkyl and dialkylaminio of 1 to 5 alkyl carbon atoms include methylamino, dimethylamino, ethylamino, diethylamino and isopropyl amino.
Examples of alkenyl and alkynyl include vinyl, allyl, 1-propenyl butenyl, pentenyl, ethynyl, propargyl, butynyl and pentynyl. Examples of acyl of 1 to 6 carbon atoms include formyl, acetyl, propionyl, butytyl, benzoyl, valeryl, hexanoyl, acryloyl, crotonoyl and carbamoyl. Examples of esterified carboxy are lower alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl.
Examples of suitable acids to form the non-toxic, pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and organic acids such as propioniic acid, acetic acid, formic acid, bezizoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic, acid, glyoxylic acid, aspartic acid, ascorbic acid, alkylmonosulfonic acids such as metlanesulfonic acid, ethanesulfonic acid and propanesulfoniic acid alkyldisulfonic acids such as methanedisulfonic acid, xcex1,xcex2-ethane-disulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids.
When R is carboxy, it can be salified by a base to form a salt of sodium, potassium, lithium, calcium, magnesium or ammonium or salts with organic bases such as methylamine, propylamine, trimethylamine, diethliylamine, triethylamine, N,N-dimethylethanolamine, tris (hydroxy-methyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, argininie, histidine and N-methylglucamine.
The alkyl, alkenyl or alkynyl can be substituted with at least one member of the group consisting of hydroxy, aryl such as phenyl or naphthyl; arylalkyl such as benzyl or phenethyl; cycloalkyl, cyclo-pentyl or cyclohexyl; alkoxy such as methoxy, ethoxy, propoxy or isopropoxy, methoxymethyl or 1-ethoxyethyl; aryloxy such as phenoxy; (aralkoxy such as benzyloxy; mercapto; alkylthio such as methylthio or ethylthio; anylthio; aralkylthio; amino such as 2-amineoethyl; substituted amino such as methylamino, ethylamino or dimethylamino; halogen i.e., chloro or bromo, such as 2-bromoethyl; nitro; azido; carbamoyl; substituted carbamoyl such as a lower N-monoalkyl carbamoyl group like N-methylcarbamoyl, N-ethylcarbamoyl, a lower N,N-dialkyl carbamoyl such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl; an N-(lower hydroxyalkyl) carbamoyl such as N-(hydroxymethyl) carbamoyl, N-(hydroxyethyl) carbamoyl, a lower carbamoylalkyl such as carbamoylmethyl, carbamoylethyl; carboxy; esterified carboxy such as methoxycarbonyl or ethoxycarbonyl; formyl; acyl such as acetyl, propionyl or benzoyl; acyloxy such as acetoxy or propionyloxy; cyano; phthlalimido; acylamido such as acetamido or benzamido; alkoxycarbonylamino such as methoxycarbonylamino or ethoxycarbonylamino; or (arylalkyl)-oxycarbonylamino such as benzyloxycarbonylamino.
A The aryl and aralkyl can be unsubstituted or substituted with at least one member of the group consisting of hydroxy; halogen; alkyl such as methyl, ethyl, isopropyl or tert-butyl; alkoxy such as methoxy, ethoxy or isopropoxy; alkylthio such as methylthio or ethylthio; nitro; amino; substituted amino such as monoalkylamino and dialkylamino such as methylamino, ethylamino or dimethylamino.
When X1, X2 or X3 are substituted alkyl or alkoxy, this is preferably substituted by at least one hydroxy, free or esterified carboxy such as methoxycarbonyl or ethoxycarbonyl, and the alkyl may be substituted by a liner or branched alkoxy of 1 to 5 carbon atoms like methoxy, ethoxy or isopropoxy.
Among the preferred compounds of formula I are those wherein X1, X2 and X3 are hydrogen, those wherein the alkyl, alkoxy, alkenyl and alkynyl are substituted with at least one member of the group consisting of xe2x80x94OH, halogen, alkoxy of 1 to 6 carbon atoms, acyl of an organic carboxylic acid of 1 to 6 carbon atoms, benzoyl, xe2x80x94CN, carboxy, carboxy esterified with an alkanol of 1 to 5 carbon atoms, unsubstituted or substituted phenyl, unsubstituted or substituted carbamoyl and 
and R6 are individually selected from the group consisting of hydrogen, alkyl of 1 to 7 carbon atoms unsubstituted or substituted by at least one member of the group consisting of xe2x80x94OH, alkoxy of 1 to 5 carbon atoms and free carboxy or esterified with alkyl of 1 to 5 carbon atoms and unsubstituted or substituted aryl of 6 to 12 carbon atoms and aralkyl of 7 to 12 carbon atoms or taken together with the nitrogen to which they are attached form a 5 to 6 member heterocycle containing or not a second heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NRA and xe2x80x94RA is selected from the group consisting of hydrogen, alkyl and hydroxy-alkyl of 1 to 5 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, unsubstituted or substituted aryl of 6 to 12 carbon atoms and unsubstituted or substituted aralkyl of 7 to 12 carbon atoms and their non-toxic, a pharmaceutically acceptable acid addition salts.
Other preferred compounds of formula I are those wherein the phenyl, aryl and aralkyl are substituted with at least one member of the group consisting of halogen, xe2x80x94OH, alkyl and alkoxy of 1 to 5 carbon atoms, CH3Sxe2x80x94, xe2x80x94NO2, xe2x80x94NH2 and monoalkyl and dialkylamino. Aralkyl of 7 to 12 carbon atoms is preferably benzyl or phenethyl unsubstituted or substituted with at least one member of the group consisting of methyl, ethyl, isopropyl, tert.-butyl, methoxy, ethoxy or propoxy.
Examples of 
as a heterocyclic are pyyrolidino, piperidino, morpholino, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl. When R5 and R6 represent the latter two, the phenyl and benzyl can be optionally substituted by the substituents already mentioned for aryl and aralkyl.
Examples of specific preferred compounds of formula I are
[16xcex1, (xc2x1)]-15-(1-propynyl)-20,21-dinoreburnamenine oxalate,
[16xcex1, (xc2x1)]-15-methyl-20, 21-dinoreburnamenine,
[16xcex1, (xc2x1)]-14,15-dihydro-15-methylene-20, 21-dinoreburnamenine acid maleate,
ethyl [16xcex1, (xc2x1)-20,21-dinoreburnamenine-15-acetate maleate,
[16xcex1, (xc2x1)-20,21-dinoreburnamenine-15-methanol acid maleate and
[16xcex1, (xc2x1)]-N,N-dimethyl-20,21-dinoreburnamenine-15-methanamine acid maleate.
The novel process of the invention for the preparation of the compounds of formula I comprises reacting a compound of the formula 
in which X1p, X2p and X3p are X1, X2 and X3 as defined above in which the reactive functions are optionally protected with
A) either a halide of the formula
Rxe2x80x2xe2x80x94V-Halxe2x80x83xe2x80x83III
xe2x80x83wherein V is magnesium or zinc and Hal is halogen or an organometallic compound of the formula
Rxe2x80x2xe2x80x94Wxe2x80x83xe2x80x83IV
xe2x80x83wherein W is lithium, sodium or potassium and Rxe2x80x2 is R either except for the free, salified or esterified carboxy or R in which the reactive functions are protected to obtain a compound of the formula 
xe2x80x83wherein Rxe2x80x2 has the above meaning and subjecting the latter to a dehydration reaction and, if necessary, to an elimination reaction of the protector groups of the reactive functions which can be carried by X1p, X2p, X3p and Rxe2x80x2 to obtain a compound of the formula 
xe2x80x83wherein X1, X2, X3 and R have the above meanings, optionally subjecting the latter when R is xe2x80x94CH2OH to the action of an oxidizing agent to obtain a product of the formula 
xe2x80x83wherein X1, X2, X3 have the above meanings and Z is hydrogen or the remainder of an ester group, which is optionally subjected to one or both of the following reactions: hydrolysis of the ester group and esterification or salification by a base of the carboxylic function.
B) or a derivative of triphenylphosphoranle of the formula 
xe2x80x83or a phosphonate of the formula 
xe2x80x83wherein R12 is alyoxy and R8 and R9 have the meanings indicated above to obtain according to the operating conditions used and optionally after elimination of the protector groups of the reactive functions which can be carried by X1p, X2p and X3p a compound of the formula 
xe2x80x83or a compound of the formula 
xe2x80x83wherein X1, X2, X3, R8 and R9 have the above meanings.
C) or an activated derivative of the product of the formula
R10xe2x80x94Cxe2x89xa1CHxe2x80x83xe2x80x83VII
xe2x80x83in which R10 as the above meaning to obtain a compound of the formula 
xe2x80x83in which X1p, X2p, X3p and R10 have the above meanings which is subjected, after activation of the hydroxyl and optional protection of the reactive functions which R10 can contain, to a reduction reaction, and optionally to an elimination reaction of the protector groups of the protected reactive functions to obtain a compound of the formula 
xe2x80x83in which X1, X2, X3 and R10 have the above menaings and optionally the products of formulae Ia1, Ia3, Ib1 and Ib2 are treated with a mineral or organic acid to obtain the corresponding salt, the said products of formula I being in all the possible racemic or enantiomeric isomer forms.
In the preferred conditions for the process of the invention, in the reaction as defined above in A), the preparation of the organomagnesium or zinc compounds of formula III and their reaction with a product of formula II can be carried out in the usual conditions known. The halogen of the magnesium or zinc halide of formula III can be bromine such as in phenylmagnesium bromide but it can also be an iodine or chlorine atom.
The preparation of the magnesium halide can be carried out, for example, by the reaction of magnesium with an organic halide in a slightly polar inert medium such as ether by the preparation process for organomagnesilm halides or Grignard reagents. The reaction of the product of formula II with the magnesium halide of formula III to obtain the products of formula V takes place preferably in an organic solvant such as ether or tetrahydrofuran at ambient temperature or under reflux.
The preparation of organometallic compounds of formula IV in which W is lithium, sodium or potassium, and their reaction with a product of formula II can be carried out in the usual conditions known. The preparation of the organolithium compound of formula IV can be effected by the reaction of an organic halide with a base such as, preferably, diisopropyllithium amide or butyllithium, for example in ether or tetrahydrofuran at a low temperature. The reaction of the product of formula II with the organolithium compound of formula IV can be effected in tetrahydrofuran or ether at a low temperature of xe2x88x9270xc2x0 C. to xe2x88x9210xc2x0 C. or also in dimethoxymethane.
The dehydration of the product of formula V to obtain a product of formula Ia1 takes place in an organic solvent which is preferably toluene or xylene, but may also be tetrahydrofuran in the presence of, for example, P2O5 or also Burgess salts. This dehydration reaction can also be effected by the activation of alcohol preferably into mesylate by methanesulfonyl chloride followed by a treatment with a strong base such as, preferably diazabicycloundecene or diazabicyclononene.
The oxidation of the product of formula Ia1 leading to the product of formula Ia2 is effected by the usual methods using for example chromium salts, selenium oxide or by operating according to Swern""s reaction. The hydrolysis of the ester group, the optional esterification or salification of the product of formula Ia2 is effected according to the usual methods.
In the reaction of B) 1), the tripheniylpliosphorane of formula VI is formed by the reaction of triphenylphosphine with the corresponding halide in which the halogen atom is preferably bromine and leading to a phosphonium salt on which a base such as potassium tert-butylate or butyllithium is reacted to obtain the expected product of formula VI. The reaction is carried out in an organic solvent such as tetrahydrofuran or ether at a temperature of between 0xc2x0 C. and reflux.
The reaction of the product of formula II with the triplienylphosphorane of formula VI to obtain a product of formula Ib1 is carried out at a temperature of between xe2x88x9270xc2x0 C. and 0xc2x0 C. The preparation of the reagent of formula VI and its reaction with the product of formula II are carried out by standard methods.
The reaction of the product of formula II and the phosphonate of formula VIxe2x80x2 to obtain the product of formula Ib1 is carried out in the presence of sodium hydride or a weak base such as sodium or potassium carbonate in a solvent such as tetrahydrofuran. When a mole to mole mixture of the product of formula II and the phosphonate of formula VIxe2x80x2 is used, the desired compounds of formula Ib1 will for the most part be obtained, while an excess of ylide and a basic medium lead for the most part to compounds of formula Ib3.
In the preferred conditions for implementing the reaction, the phosphorated derivative used to obtain compounds of formula Ib1 in which R8 and R9 are an optionally substituted alkyl or phenyl is a phosphorane. In the cases where R8 and R9 contain one or more ester, cyano or acyl, the phosphorus-containing derivative used is preferably a phosphonate.
In the reaction as in C) of the product of formula II with an acetylene derivative of formula VII to obtain a compound of formula VIII, the acetylene derivative such as acetylene or propyne is activated in anion form in a basic medium, for example of sodium or potassium alkanoate such as potassium tert-butanoate or of a lithium-containing base such as butyllithium. The reaction takes place in an organic solvent such as tetrahydrofuran or ether. In the reaction as in C), the reduction of the product of formula VIII is carried out with a hydride, notably a mixed hydride, such as lithium and aluminum mixed hydride or sodium and aluminum diethyl-hydride. Sodium or potassium borohydride can also be used as the reagent as well as sodium cyanoborohydride in the presence of an alcohol such as for example methanol or ethanol.
The activation of the hydroxyl function of the compound of formula VIII can be effected for example by a halide such as, preferably, methanesulfonyl chloride in a basic medium, for example triethylamine or pyridine in an organic solvent such as tetrahydrofuran or dichloromethane. The reduction reaction of the activated compound of formula VIII to obtain tht compounds of formula Ib2 is preferably effected in anhydrous conditions, for example with a lithium and aluminum hydride in tetrahydrofuran or ether.
In the case where R10 contains one or more esterified carboxy functions, these can, by reduction of the compound of formula VIII, be converted into alcohol functions, and in this case these alcohol functions can be optionally re-oxidized to produce the initial esterified carboxy functions. This re-oxidization can be effected by chromium oxide or chromium salts such as pyridinium dichromate or pyridinium chlorochromate in a solvent such as dichloromethane or dimethylformamide.
The process for the preparation of the compounds of formula I wherein 
wherein R7 is methyl unsubstituted or substituted with xe2x80x94OH or halogen or free, esterified or salified carboxy or 
and R5 and R6 are defined as above comprises reacting a compound of the formula 
wherein X1p, X2p, and X3p have the above definitions with a halogenated derivative of methyloxosulfonium of the formula 
in a basic medium to obtain the corresponding epoxide of the formula 
wherein X1p, X2 and X3 have the above meanings and reacting the latter either with a base to obtain the corresponding alcohol of the formula 
in which X1p, X2p and X3p have the above meanings and optionally subjecting the latter to an elimination reaction of the protector groups of the reactive functions that can be carried by X1p, X2p and X3p to produce a product of the formula 
in which X1, X2 and X3 have the above meanings and optionally treating the latter with an oxidizing agent to obtain a product of the formula 
in which X1, X2 X3 and Z have the above meanings which is optionally subjected to one or both of the following reactions: hydrolysis of the ester group and esterification or salification by a base of the carboxy function,
or with an amine of the formula 
in which R5 and R6 have the above meanings to obtain a compound of the formula 
in which X1p, X2p and X3p have the above meanings, the said compounds of formula Xxe2x80x2 and XII being subjected, after activation of the hydroxyl either, if desired in the case of compound Xxe2x80x2, to a reaction with the amine of formula XI as defined above, or, in the case of compound XII to a dehydration reaction to obtain in these two cases and after elimination, if necessary, of the protector groups of the reactive functions which can be carried by X1p, X2p and X3p a compound of the formula 
in which X1, X2, X3, R5 and R6 have the above meanings or with a tetrabutylammonium halide to obtain a product of the formula 
in which Hal is halogen, then subjecting the latter to a dehydration reaction to obtain, after elimination if necessary of the protector groups or the reactive functions which can be carried by X1p, X2p and X3p a compound of the formula 
in which X1, X2, X3 and Hal have the above meaning, and if desired the products of formulae Ia3, Ia5 and Ia6 are treated with a mineral or organic acid to obtain the corresponding acid addition salt, the said products of formula I being in all the possible racemic and enantiomeric isomer forms.
In the preferred mode of the process of the invention, the reaction of the product of formula II with the halogenated derivative of methyloxosulfonium of formula IX, such as for example trimethyloxosulfonium iodide to obtain the compounds of formula X is carried out in a basic medium, for example potassium tert-butylate or butyllithium in the presence of an organic solvent such as tetrahydrofuran or ether.
The start of the reaction of epoxide of formula X leading to the product of formula Xxe2x80x2 is carried out for example in a solution of lithium diisopropylamide in tetrahydrofuran at a temperature of about xe2x88x9270xc2x0 C., which is then allowed to return to ambient temperature.
The oxidation of the product of formula Ia4 leading to the product of formula Ia2 is carried out as indicated above for the oxidation of the products Ia1. The hyrolysis of the ester group, the optional esterification or salification are carried out according to known methods.
The starting reaction of the epoxide of formula X with the addition of the amnine of formula XI leading to the compound of formula XII is carried out in an alcohol solvent such as methanol or ethanol at reflux of the alcohol used.
The hydroxyl of the compounds of formula Xxe2x80x2 and XII can be activated using for example mesyl chloride or trifluoroacetyl chloride in a solution of tetrahydrofuran in the presence of a base such as pyridine or triethylamine. The dehydration of the activated compound of formula XII leading to the product of formula Ia5 is carried out in an organic solvent such as toluene in the presence of a strong base such as diazabicycloundecene or diazabicyclononene at reflux. The product of formula Ia5 can also be obtained by the addition of the amine of formula XI on the activated compound of formula Xxe2x80x2. The reaction takes place in a solvent such as toluene or xylene or an alcohol such as methanol or ethanol, the mixture being taken to reflux.
The halide which is used to obtain a product of formula XIII is for example tetrabutylammonium fluoride in an organic solvent.
The process of the invention for the preparation of a compound of formula I wherein 
wherein R11 is xe2x80x94Cxe2x89xa1Cxe2x80x94R10 and R10 is defined as above comprises reacting a compound of the formula 
wherein X1p, X2p, X3p and R10 have the above meaning after activation of the hydroxyl with a dehydration agent to obtain, after elimination, if necessary and if desired, of the protector groups of the reactive functions which can be carried by X1p, X2p and X3p a compound of the enyne type of the formula 
wherein X1, X2, X3 and R10 have the above meanings and if desired the latter product is treated with a mineral or organic acid, the said products of formula I being in all the possible racemic or enantiomeric isomer forms.
The dehydration reaction of the compound of formula VIII activated on the hydroxyl, for example, into the mesylate or acetate, is carried out preferably in an organic solvent such as toluene in the presence of a base such as diazabicyclo-undecene or diazabicyclononene. The various reactive functions which can be carried by certain compounds above can, if necessary, be protected: for example free hydroxyl, acyl, or carboxy or amino and monoalkylamino which can be protected by the appropriate protectors.
The following non-exhaustive list of examples of protection of reactive functions can be cited: the hydroxy groups can be protected for example by trimethylsilyl, tert-butyldimethylsilyl, dihydropyran or metlhoxymethyl; the amino groups can be protected for example by trityl, benzyl, tert-butoxycarbonyl, or phthalimido or by other groups known in the chemistry of peptides; the acyl groups such as formyl can be protected for example in the form of cyclic or non-cyclic ketals such as dimethyl- or diethyl ketal or ethylene dioxyketal; and the carboxys can be protected for example in the form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters.
The elimination of these protectors groups is carried out under the usual conditions known to a man of the art, notably acid hydrolysis carried out with an acid such as one of the following acids: hydrochloric acid, benzene sulfonic acid, or para-toluene sulfonic acid, formic acid or trifluoroacetic acid. The phthalimido group is eliminated by hydrazine. A list of the various usable protector groups will be found for example in Pat. No. 2,499,995.
The optically active forms of the products of formula I can be recovered by resolution of the racemates by the usual methods or using as starting products, products of formula II in optically active forms.
The novel pharmaceutical compositions of the invention are comprised of a pharmaceutically effective amount of at least one compound of formula I or its salts and an inert carrier. The compositions may be in the form of tablets, dragees, capsules, granules, suppositories, ointments, creams, gels, aerosols and injectable solutions or suspensions.
Examples of suitable excipients are talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, and preservatives.
The compositions have an affinity for the adrenergic alpha2 receptors and also have useful anti-amnesic, neuronal protective anti-depressant, anti-anoxic or anti-ischemic properties. They can be used in the treatment of cerebral insufficiencies of anoxic or ischemic origin, of menory and attention disorders as well as can be used as anti-depressants.
The novel method of the invention comprises administering to warm-blooded animals, including humans, an effective amount of at least one compound of formula I and its salts. The compounds may be administered orally, rectally, buccally, parenterally or topically to the skin and mucous membrane. The usual daily dose is 0.1333 to 2.666 mg/kg depending on the condition treated, the method of administration and the specific compound.
The starting compound of formula IIa in which X1, X2 and X3 are hydrogen is described in U.S. Patent No. 4,382,936. The starting compounds of the formula 
in which X1xe2x80x2, X2xe2x80x2 and X3xe2x80x2are individually X1, X2 and X3 and at least one of X1xe2x80x2, X2xe2x80x2, and X3xe2x80x2, is not hydrogen can be prepared by the process described in the said patent starting from corresponding substituted tryptamines.
Another process for the products of formula IIxe2x80x2 as defined above consists of subjecting the product of the formula 
to a nitration reaction to obtain a product of formula 
which is reduced, if appropriate, to obtain a product of the formula 
which, if appropriate either is subjected to an alkylation or acylation reaction, or is converted to a diazonium salt from which there is prepared by known processes, the derivatives of the formula 
wherein Z is halogen or an optionally substituted hydroxy or phenyl, which are converted, if appropriate, into corresponding derivatives in which Z is alkyloxy or alkyl.
Finally as new industrial products as intermediates necessary for the preparation of products of formula I are the compounds of the formula 
in which X1xe2x80x3, X2xe2x80x3 and X3xe2x80x3 are individually X1, X2 and X3, except for the products in which one of the substituents X1xe2x80x3, X2xe2x80x3 and X3xe2x80x3 is hydrogen and the other two are individually chosen from hydrogen or halogen, alkyl or alkoxy of 1 to 5 carbon atoms, hydroxy, trifluoromethyl or nitro and the compounds of formulae V, VIII, X, Xxe2x80x2, XII and XIII.